CLINICAL PHARMACOLOGY SECTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Lansoprazole belongs to a class of antisecretory compounds, the substituted benzimidazoles, that suppress gastric acid secretion by specific inhibition of the (H+, K+)-ATPase enzyme system at the secretory surface of the gastric parietal cell. Because this enzyme system is regarded as the acid (proton) pump within the parietal cell, lansoprazole has been characterized as a gastric acid-pump inhibitor, in that it blocks the final step of acid production. This effect is dose-related and leads to inhibition of both basal and stimulated gastric acid secretion irrespective of the stimulus. Lansoprazole does not exhibit anticholinergic or histamine type-2 antagonist activity.

12.2 Pharmacodynamics

Antisecretory Activity

After oral administration, lansoprazole was shown to significantly decrease the basal acid output and significantly increase the mean gastric pH and percent of time the gastric pH was greater than three and greater than four. Lansoprazole also significantly reduced meal-stimulated gastric acid output and secretion volume, as well as pentagastrin-stimulated acid output. In patients with hypersecretion of acid, lansoprazole significantly reduced basal and pentagastrin-stimulated gastric acid secretion. Lansoprazole inhibited the normal increases in secretion volume, acidity and acid output induced by insulin.

The intragastric pH results of a five day, pharmacodynamic, crossover study of 15 and 30 mg of once daily lansoprazole are presented in Table 6:

After the initial dose in this study, increased gastric pH was seen within one to two hours with 30 mg of lansoprazole and two to three hours with 15 mg of lansoprazole. After multiple daily dosing, increased gastric pH was seen within the first hour postdosing with 30 mg of lansoprazole and within one to two hours postdosing with 15 mg of lansoprazole.

Acid suppression may enhance the effect of antimicrobials in eradicating Helicobacter pylori (H. pylori). The percentage of time gastric pH was elevated above five and six was evaluated in a crossover study of lansoprazole given daily, twice daily and three times daily (Table 7).

The inhibition of gastric acid secretion as measured by intragastric pH gradually returned to normal over two to four days after multiple doses. There was no indication of rebound gastric acidity.

Enterochromaffin-like (ECL) Cell Effects

During lifetime exposure of rats with up to 150 mg/kg/day of lansoprazole dosed seven days per week, marked hypergastrinemia was observed followed by ECL cell proliferation and formation of carcinoid tumors, especially in female rats. Gastric biopsy specimens from the body of the stomach from approximately 150 patients treated continuously with lansoprazole for at least one year did not show evidence of ECL cell effects similar to those seen in rat studies. Longer term data are needed to rule out the possibility of an increased risk of the development of gastric tumors in patients receiving long-term therapy with lansoprazole [see Nonclinical Toxicology (13.1)].

Other Gastric Effects in Humans

Lansoprazole did not significantly affect mucosal blood flow in the fundus of the stomach. Due to the normal physiologic effect caused by the inhibition of gastric acid secretion, a decrease of about 17% in blood flow in the antrum, pylorus, and duodenal bulb was seen. Lansoprazole significantly slowed the gastric emptying of digestible solids. Lansoprazole increased serum pepsinogen levels and decreased pepsin activity under basal conditions and in response to meal stimulation or insulin injection. As with other agents that elevate intragastric pH, increases in gastric pH were associated with increases in nitrate-reducing bacteria and elevation of nitrite concentration in gastric juice in patients with gastric ulcer. No significant increase in nitrosamine concentrations was observed.

Serum Gastrin Effects

In over 2100 patients, median fasting serum gastrin levels increased 50 to 100% from baseline but remained within normal range after treatment with 15 to 60 mg of oral lansoprazole. These elevations reached a plateau within two months of therapy and returned to pretreatment levels within four weeks after discontinuation of therapy.

Increased gastrin causes enterochromaffin-like cell hyperplasia and increased serum CgA levels. The increased CgA levels may cause false positive results in diagnostic investigations for neuroendocrine tumors [see Warnings and Precautions (5.9)].

Endocrine Effects

Human studies for up to one year have not detected any clinically significant effects on the endocrine system. Hormones studied include testosterone, luteinizing hormone (LH), follicle stimulating hormone (FSH), sex hormone binding globulin (SHBG), dehydroepiandrosterone sulfate (DHEA-S), prolactin, cortisol, estradiol, insulin, aldosterone, parathormone, glucagon, thyroid stimulating hormone (TSH), triiodothyronine (T3), thyroxine (T4), and somatotropic hormone (STH). Lansoprazole in oral doses of 15 to 60 mg for up to one year had no clinically significant effect on sexual function. In addition, lansoprazole in oral doses of 15 to 60 mg for two to eight weeks had no clinically significant effect on thyroid function. In 24 month carcinogenicity studies in Sprague-Dawley rats with daily lansoprazole dosages up to 150 mg/kg, proliferative changes in the Leydig cells of the testes, including benign neoplasm, were increased compared to control rats.

Other Effects

No systemic effects of lansoprazole on the central nervous system, lymphoid, hematopoietic, renal, hepatic, cardiovascular, or respiratory systems have been found in humans. Among 56 patients who had extensive baseline eye evaluations, no visual toxicity was observed after lansoprazole treatment (up to 180 mg/day) for up to 58 months. After lifetime lansoprazole exposure in rats, focal pancreatic atrophy, diffuse lymphoid hyperplasia in the thymus, and spontaneous retinal atrophy were seen.

12.3 Pharmacokinetics

Absorption

Lansoprazole delayed-release orally disintegrating tablets contain an enteric- coated pellets formulation of lansoprazole (because lansoprazole is acid- labile), so that absorption of lansoprazole begins only after the pellets leave the stomach. The mean peak plasma levels of lansoprazole occur at approximately 1.7 hours. After a single-dose administration of 15 to 60 mg of oral lansoprazole, the peak plasma concentrations (Cmax) of lansoprazole and the area under the plasma concentration curves (AUCs) of lansoprazole were approximately proportional to the administered dose. Lansoprazole does not accumulate and its pharmacokinetics are unaltered by multiple dosing. The absolute bioavailability is over 80%. In healthy subjects, the mean (± SD) plasma half-life was 1.5 (± 1.0) hours. Both the Cmax and AUC are diminished by about 50 to 70% if lansoprazole is given 30 minutes after food, compared to the fasting condition. There is no significant food effect if lansoprazole is given before meals.

Distribution

Lansoprazole is 97% bound to plasma proteins. Plasma protein binding is constant over the concentration range of 0.05 to 5 mcg/mL.

Elimination

Metabolism

Lansoprazole is extensively metabolized in the liver. Two metabolites have been identified in measurable quantities in plasma (the hydroxylated sulfinyl and sulfone derivatives of lansoprazole). These metabolites have very little or no antisecretory activity. Lansoprazole is thought to be transformed into two active species which inhibit acid secretion by blocking the proton pump [(H+, K+)-ATPase enzyme system] at the secretory surface of the gastric parietal cell. The two active species are not present in the systemic circulation. The plasma elimination half-life of lansoprazole is less than two hours while the acid inhibitory effect lasts more than 24 hours. Therefore, the plasma elimination half-life of lansoprazole does not reflect its duration of suppression of gastric acid secretion.

Excretion

Following single-dose oral administration of lansoprazole, virtually no unchanged lansoprazole was excreted in the urine. In one study, after a single oral dose of 14C-lansoprazole, approximately one-third of the administered radiation was excreted in the urine and two-thirds was recovered in the feces. This implies a significant biliary excretion of the lansoprazole metabolites.

Specific Populations

Pediatric Patients

One to 17 Years of Age

The pharmacokinetics of lansoprazole were studied in pediatric patients with GERD aged one to 11 years and 12 to 17 years in two separate clinical studies. In children aged one to 11 years, lansoprazole was dosed 15 mg daily for subjects weighing ≤ 30 kg and 30 mg daily for subjects weighing greater than 30 kg. Mean Cmax and AUC values observed on Day 5 of dosing were similar between the two dose groups and were not affected by weight or age within each weight-adjusted dose group used in the study. In adolescent subjects aged 12 to 17 years, subjects were randomized to receive lansoprazole at 15 or 30 mg daily. Mean Cmax and AUC values of lansoprazole were not affected by body weight or age; and nearly dose-proportional increases in mean Cmax and AUC values were observed between the two dose groups in the study. Overall, lansoprazole pharmacokinetics in pediatric patients aged one to 17 years were similar to those observed in healthy adult subjects.

Geriatric Patients

The clearance of lansoprazole is decreased in the elderly, with elimination half-life increased approximately 50 to 100%. Because the mean half-life in the elderly remains between 1.9 to 2.9 hours, repeated once daily dosing does not result in accumulation of lansoprazole. Peak plasma levels were not increased in the elderly [see Use in Specific Populations (8.5)].

Male and Female Patients

In a study comparing 12 male and six female human subjects who received lansoprazole, no sex-related differences were found in pharmacokinetics and intragastric pH results.

Racial or Ethnic Groups

The pooled mean pharmacokinetic parameters of lansoprazole from twelve U.S. studies (N = 513) were compared to the mean pharmacokinetic parameters from two Asian studies (N = 20). The mean AUCs of lansoprazole in Asian subjects were approximately twice those seen in pooled U.S. data; however, the inter- individual variability was high. The Cmax values were comparable.

Patients with Renal Impairment

In patients with severe renal impairment, plasma protein binding decreased by 1 to 1.5% after administration of 60 mg of lansoprazole. Patients with renal impairment had a shortened elimination half-life and decreased total AUC (free and bound). The AUC for free lansoprazole in plasma, however, was not related to the degree of renal impairment; and the Cmax and Tmax (time to reach the maximum concentration) were not different than the Cmax and Tmax from subjects with normal renal function. Therefore, the pharmacokinetics of lansoprazole were not clinically different in patients with mild, moderate or severe renal impairment compared to healthy subjects with normal renal function.

Patients with Hepatic Impairment

In patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment there was an approximate 3-fold increase in mean AUC compared to healthy subjects with normal hepatic function following multiple oral doses of 30 mg lansoprazole for seven days. The corresponding mean plasma half-life of lansoprazole was prolonged from 1.5 to four hours (Child-Pugh A) or five hours (Child-Pugh B).

In patients with compensated and decompensated cirrhosis, there was an approximate 6- and 5-fold increase in AUC, respectively, compared to healthy subjects with normal hepatic function following a single oral dose of 30 mg lansoprazole [see Dosage and Administration (2.3), Use in Specific Populations (8.6)].

Drug Interaction Studies

Effect of Lansoprazole on Other Drugs

Cytochrome P450 Interactions

Lansoprazole is metabolized through the cytochrome P450 system, specifically through the CYP3A and CYP2C19 isozymes. Studies have shown that lansoprazole does not have clinically significant interactions with other drugs metabolized by the cytochrome P450 system, such as warfarin, antipyrine, indomethacin, ibuprofen, phenytoin, propranolol, prednisone, diazepam, or clarithromycin in healthy subjects. These compounds are metabolized through various cytochrome P450 isozymes including CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A.

Theophylline

When lansoprazole was administered concomitantly with theophylline (CYP1A2, CYP3A), a minor increase (10%) in the clearance of theophylline was seen. Because of the small magnitude and the direction of the effect on theophylline clearance, this interaction is unlikely to be of clinical concern [see Drug Interactions (7)].

Methotrexate and 7-hydroxymethotrexate

In an open-label, single-arm, eight day, pharmacokinetic study of 28 adult rheumatoid arthritis patients (who required the chronic use of 7.5 to 15 mg of methotrexate given weekly), administration of seven days of naproxen 500 mg twice daily and lansoprazole 30 mg daily had no effect on the pharmacokinetics of methotrexate and 7-hydroxymethotrexate. While this study was not designed to assess the safety of this combination of drugs, no major adverse reactions were noted. However, this study was conducted with low doses of methotrexate. A drug interaction study with high doses of methotrexate has not been conducted [see Warnings and Precautions (5.10)].

Amoxicillin

Lansoprazole has also been shown to have no clinically significant interaction with amoxicillin.

Sucralfate

In a single-dose crossover study examining lansoprazole 30 mg administered alone and concomitantly with sucralfate 1 gram, absorption of lansoprazole was delayed and the bioavailability was reduced by 17% when administered concomitantly with sucralfate [see Dosage and Administration (2.4), Drug Interactions (7)].

Antacids

In clinical trials, antacids were administered concomitantly with lansoprazole and there was no evidence of a change in the efficacy of lansoprazole.

Clopidogrel

Clopidogrel is metabolized to its active metabolite in part by CYP2C19. A study of healthy subjects who were CYP2C19 extensive metabolizers, receiving once daily administration of clopidogrel 75 mg alone or concomitantly with lansoprazole 30 mg (n = 40), for nine days was conducted. The mean AUC of the active metabolite of clopidogrel was reduced by approximately 14% (mean AUC ratio was 86%, with 90% CI of 80 to 92%) when lansoprazole was coadministered compared to administration of clopidogrel alone.

Pharmacodynamic parameters were also measured and demonstrated that the change in inhibition of platelet aggregation (induced by 5 mcM ADP) was related to the change in the exposure to clopidogrel active metabolite. The effect on exposure to the active metabolite of clopidogrel and on clopidogrel-induced platelet inhibition is not considered clinically important.

Effect of Other Drugs on Lansoprazole

Because lansoprazole is metabolized by CYP2C19 and CYP3A4, inducers and inhibitors of these enzymes may potentially alter exposure of lansoprazole.

12.4 Microbiology

Microbiology

Lansoprazole, clarithromycin and/or amoxicillin have been shown to be active against most strains of Helicobacter pylori in vitro and in clinical infections [see Indications and Usage (1.2)].

Helicobacter pylori Pretreatment Resistance

Clarithromycin pretreatment resistance (≥ 2.0 mcg/mL) was 9.5% (91/960) by E-test and 11.3% (12/106) by agar dilution in the dual and triple therapy clinical trials (M93-125, M93-130, M93-131, M95-392, and M95-399).

Amoxicillin pretreatment susceptible isolates (≤ 0.25 mcg/mL) occurred in 97.8% (936/957) and 98.0% (98/100) of the patients in the dual and triple therapy clinical trials by E-test and agar dilution, respectively. Twenty-one of 957 patients (2.2%) by E-test, and two of 100 patients (2.0%) by agar dilution, had amoxicillin pretreatment MICs of greater than 0.25 mcg/mL. One patient on the 14 day triple therapy regimen had an unconfirmed pretreatment amoxicillin minimum inhibitory concentration (MIC) of greater than 256 mcg/mL by E-test and the patient was eradicated of H. pylori (Table 8).

Patients not eradicated of H. pylori following lansoprazole/amoxicillin/clarithromycin triple therapy will likely have clarithromycin resistant H. pylori. Therefore, for those patients who fail therapy, clarithromycin susceptibility testing should be done when possible. Patients with clarithromycin resistant H. pylori should not be treated with lansoprazole/amoxicillin/clarithromycin triple therapy or with regimens which include clarithromycin as the sole antimicrobial agent.

**Amoxicillin Susceptibility Test Results and Clinical/Bacteriological

Outcomes**

In the dual and triple therapy clinical trials, 82.6% (195/236) of the patients that had pretreatment amoxicillin susceptible MICs (≤ 0.25 mcg/mL) were eradicated of H. pylori. Of those with pretreatment amoxicillin MICs of greater than 0.25 mcg/mL, three of six had the H. pylori eradicated. A total of 30% (21/70) of the patients failed lansoprazole 30 mg three times daily/amoxicillin 1 g three times daily dual therapy and a total of 12.8% (22/172) of the patients failed the 10 and 14 day triple therapy regimens. Post-treatment susceptibility results were not obtained on 11 of the patients who failed therapy. Nine of the 11 patients with amoxicillin post-treatment MICs that failed the triple therapy regimen also had clarithromycin resistant H. pylori isolates.

Susceptibility Test for Helicobacter pylori

For susceptibility testing information about Helicobacter pylori, see Microbiology section in prescribing information for clarithromycin and amoxicillin.

DOSAGE & ADMINISTRATION SECTION

Highlight: Recommended Dosage:

•

See full prescribing information for complete dosing information for lansoprazole delayed-release orally disintegrating tablets by indication and age group and dosage adjustment in patients with severe hepatic impairment. (2.1, 2.2, 2.3)

Administration Instructions (2.4):

Lansoprazole Delayed-Release Orally Disintegrating Tablets

•

Should not be broken or cut.

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Should not be chewed.

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Place the tablet on the tongue and allow it to disintegrate, with or without water, until the pellets can be swallowed.

•

See full prescribing information for alternative administration options.

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Adult Dosage by Indication

2.2 Recommended Pediatric Dosage by Indication

Pediatric Patients 1 to 11 Years of Age

In clinical studies, lansoprazole delayed-release orally disintegrating tablets were not administered beyond 12 weeks in 1 to 11 year olds. It is not known if lansoprazole delayed-release orally disintegrating tablets are safe and effective if used longer than the recommended duration. Do not exceed the recommended dose and duration of use in pediatric patients as outlined below [see Use in Specific Populations (8.4)].

Pediatric Patients 12 to 17 Years of Age

2.3 Hepatic Impairment

The recommended dosage is 15 mg orally daily in patients with severe liver impairment (Child-Pugh C) [see Use in Specific Populations (8.6)].

2.4 Important Administration Information

•

Take lansoprazole delayed-release orally disintegrating tablets before meals.

•

Do not crush or chew lansoprazole delayed-release orally disintegrating tablets.

•

Take lansoprazole delayed-release orally disintegrating tablets at least 30 minutes prior to sucralfate [see Drug Interactions (7)].

•

Antacids may be used concomitantly with lansoprazole delayed-release orally disintegrating tablets.

•

Missed doses: If a dose is missed, administer as soon as possible. However, if the next scheduled dose is due, do not take the missed dose, and take the next dose on time. Do not take two doses at one time to make up for a missed dose.

Lansoprazole Delayed-Release Orally Disintegrating Tablets

•

Do not break or cut.

•

Place the tablet on the tongue, allow it to disintegrate, with or without water, until the pellets can be swallowed. Do not chew the pellets.

•

The tablet typically disintegrates in less than one minute.

•

Alternatively, for children or other patients who have difficulty swallowing tablets, lansoprazole delayed-release orally disintegrating tablets can be administered with water via oral syringe or NG tube as follows:

Administration with Water in an Oral Syringe

Place a 15 mg tablet in oral syringe and draw up 4 mL of water, or place a 30 mg tablet in oral syringe and draw up 10 mL of water.

Shake gently to allow for a quick dispersal.

After the tablet has dispersed, administer the contents within 15 minutes of mixing into the mouth. Do not save the water and pellets mixture for later use.

Refill the syringe with approximately 2 mL (5 mL for the 30 mg tablet) of water, shake gently, and administer any remaining contents.

Administration with Water via a NG Tube (≥ 8 French)

Place a 15 mg tablet in a catheter-tip syringe and draw up 4 mL of water, or place a 30 mg tablet in a catheter-tip syringe and draw up 10 mL of water.

Shake gently to allow for a quick dispersal.

After the tablet has dispersed, shake the catheter-tip syringe gently in order to keep the pellets from settling, and immediately inject the mixture through the NG tube into the stomach within 15 minutes of mixing. Do not save the water and pellets mixture for later use.

Refill the catheter-tip syringe with approximately 5 mL of water, shake gently, and flush the tube. 

DOSAGE FORMS & STRENGTHS SECTION

Highlight: •

Delayed-release orally disintegrating tablets: 15 mg and 30 mg. (3) 

3 DOSAGE FORMS AND STRENGTHS

Lansoprazole Delayed-Release Orally Disintegrating Tablets are available containing 15 mg or 30 mg of lansoprazole, USP.

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15 mg tablets are pale yellow, round, flat-faced, speckled, unscored tablets debossed with**M** on one side of the tablet and**LP1** on the other side.

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30 mg tablets are pale yellow, round, flat-faced, speckled, unscored tablets debossed with**M** on one side of the tablet and**LP2** on the other side.

CONTRAINDICATIONS SECTION

Highlight: •

Contraindicated in patients with known hypersensitivity to any component of the lansoprazole delayed-release orally disintegrating tablet formulation. (4)

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Patients receiving rilpivirine-containing products. (4, 7)

4 CONTRAINDICATIONS

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Lansoprazole delayed-release orally disintegrating tablets are contraindicated in patients with known hypersensitivity to any component of the formulation. Hypersensitivity reactions may include anaphylaxis, anaphylactic shock, angioedema, bronchospasm, acute tubulointerstitial nephritis, and urticaria [see Warnings and Precautions (5.2), Adverse Reactions (6)].

•

Proton Pump Inhibitors (PPIs), including lansoprazole delayed-release orally disintegrating tablets, are contraindicated with rilpivirine-containing products [see Drug Interactions (7)].

•

For information about contraindications of antibacterial agents (clarithromycin and amoxicillin) indicated in combination with lansoprazole delayed-release orally disintegrating tablets, refer to the Contraindications section of their prescribing information.

ADVERSE REACTIONS SECTION

Highlight: Most commonly reported adverse reactions (≥ 1%): diarrhea, abdominal pain, nausea and constipation. (6)

**To report SUSPECTED ADVERSE REACTIONS, contactMylan at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or **www.fda.gov/medwatch.

6 ADVERSE REACTIONS

The following serious adverse reactions are described below and elsewhere in labeling:

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Acute Tubulointerstitial Nephritis [see Warnings and Precautions (5.2)]

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 Clostridium difficile-Associated Diarrhea [see Warnings and Precautions (5.3)]

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Bone Fracture [see Warnings and Precautions (5.4)]

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Severe Cutaneous Adverse Reactions [see Warnings and Precautions (5.5)]

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Cutaneous and Systemic Lupus Erythematosus [see Warnings and Precautions (5.6)]

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Cyanocobalamin (Vitamin B12) Deficiency [see Warnings and Precautions (5.7)]

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Hypomagnesemia and Mineral Metabolism [see Warnings and Precautions (5.8)]

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Fundic Gland Polyps [see Warnings and Precautions (5.12)]

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Worldwide, over 10,000 patients have been treated with lansoprazole in Phase 2 or Phase 3 clinical trials involving various dosages and durations of treatment. In general, lansoprazole treatment has been well-tolerated in both short-term and long-term trials.

The following adverse reactions were reported by the treating physician to have a possible or probable relationship to drug in 1% or more of lansoprazole-treated patients and occurred at a greater rate in lansoprazole- treated patients than placebo-treated patients in Table 1.

Headache was also seen at greater than 1% incidence but was more common on placebo. The incidence of diarrhea was similar between patients who received placebo and patients who received 15 and 30 mg of lansoprazole, but higher in the patients who received 60 mg of lansoprazole (2.9, 1.4, 4.2, and 7.4%, respectively).

The most commonly reported possibly or probably treatment-related adverse event during maintenance therapy was diarrhea.

In the risk reduction study of lansoprazole for NSAID-associated gastric ulcers, the incidence of diarrhea for patients treated with lansoprazole, misoprostol, and placebo was 5, 22, and 3%, respectively.

Another study for the same indication, where patients took either a COX-2 inhibitor or lansoprazole and naproxen, demonstrated that the safety profile was similar to the prior study. Additional reactions from this study not previously observed in other clinical trials with lansoprazole included contusion, duodenitis, epigastric discomfort, esophageal disorder, fatigue, hunger, hiatal hernia, hoarseness, impaired gastric emptying, metaplasia, and renal impairment.

Additional adverse experiences occurring in less than 1% of patients or subjects who received lansoprazole in domestic trials are shown below:

Body as a Whole: abdomen enlarged, allergic reaction, asthenia, back pain, candidiasis, carcinoma, chest pain (not otherwise specified), chills, edema, fever, flu syndrome, halitosis, infection (not otherwise specified), malaise, neck pain, neck rigidity, pain, pelvic pain

Cardiovascular System: angina, arrhythmia, bradycardia, cerebrovascular accident/cerebral infarction, hypertension/hypotension, migraine, myocardial infarction, palpitations, shock (circulatory failure), syncope, tachycardia, vasodilation

Digestive System: abnormal stools, anorexia, bezoar, cardiospasm, cholelithiasis, colitis, dry mouth, dyspepsia, dysphagia, enteritis, eructation, esophageal stenosis, esophageal ulcer, esophagitis, fecal discoloration, flatulence, gastric nodules/fundic gland polyps, gastritis, gastroenteritis, gastrointestinal anomaly, gastrointestinal disorder, gastrointestinal hemorrhage, glossitis, gum hemorrhage, hematemesis, increased appetite, increased salivation, melena, mouth ulceration, nausea and vomiting, nausea and vomiting and diarrhea, gastrointestinal moniliasis, rectal disorder, rectal hemorrhage, stomatitis, tenesmus, thirst, tongue disorder, ulcerative colitis, ulcerative stomatitis

Endocrine System: diabetes mellitus, goiter, hypothyroidism

Hemic and Lymphatic System: anemia, hemolysis, lymphadenopathy

Metabolism and Nutritional Disorders: avitaminosis, gout, dehydration, hyperglycemia/hypoglycemia, peripheral edema, weight gain/loss

Musculoskeletal System: arthralgia, arthritis, bone disorder, joint disorder, leg cramps, musculoskeletal pain, myalgia, myasthenia, ptosis, synovitis

Nervous System: abnormal dreams, agitation, amnesia, anxiety, apathy, confusion, convulsion, dementia, depersonalization, depression, diplopia, dizziness, emotional lability, hallucinations, hemiplegia, hostility aggravated, hyperkinesia, hypertonia, hypesthesia, insomnia, libido decreased/increased, nervousness, neurosis, paresthesia, sleep disorder, somnolence, thinking abnormality, tremor, vertigo

Respiratory System: asthma, bronchitis, cough increased, dyspnea, epistaxis, hemoptysis, hiccup, laryngeal neoplasia, lung fibrosis, pharyngitis, pleural disorder, pneumonia, respiratory disorder, upper respiratory inflammation/infection, rhinitis, sinusitis, stridor

Skin and Appendages: acne, alopecia, contact dermatitis, dry skin, fixed eruption, hair disorder, maculopapular rash, nail disorder, pruritus, rash, skin carcinoma, skin disorder, sweating, urticaria

Special Senses: abnormal vision, amblyopia, blepharitis, blurred vision, cataract, conjunctivitis, deafness, dry eyes, ear/eye disorder, eye pain, glaucoma, otitis media, parosmia, photophobia, retinal degeneration/disorder, taste loss, taste perversion, tinnitus, visual field defect

Urogenital System: abnormal menses, breast enlargement, breast pain, breast tenderness, dysmenorrhea, dysuria, gynecomastia, impotence, kidney calculus, kidney pain, leukorrhea, menorrhagia, menstrual disorder, penis disorder, polyuria, testis disorder, urethral pain, urinary frequency, urinary retention, urinary tract infection, urinary urgency, urination impaired, vaginitis

6.2 Postmarketing Experience

Additional adverse experiences have been reported since lansoprazole delayed- release orally disintegrating tablets have been marketed. The majority of these cases are foreign-sourced and a relationship to lansoprazole delayed- release orally disintegrating tablets has not been established. Because these reactions were reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events are listed below by COSTART body system.

Body as a Whole: anaphylactic/anaphylactoid reactions, systemic lupus erythematosus;

Digestive System: hepatotoxicity, pancreatitis, vomiting;

Hemic and Lymphatic System: agranulocytosis, aplastic anemia, hemolytic anemia, leukopenia, neutropenia, pancytopenia, thrombocytopenia, and thrombotic thrombocytopenic purpura;

Infections and Infestations: Clostridium difficile-associated diarrhea;

Metabolism and Nutritional Disorders: hypomagnesemia, hypocalcemia, hypokalemia, hyponatremia;

Musculoskeletal System: bone fracture, myositis;

Skin and Appendages: severe dermatologic reactions including erythema multiforme, SJS/TEN (some fatal), DRESS, AGEP, cutaneous lupus erythematosus;

Special Senses: speech disorder;

Urogenital System: interstitial nephritis, urinary retention.

6.3 Combination Therapy with Amoxicillin and Clarithromycin

In clinical trials using combination therapy with lansoprazole plus amoxicillin and clarithromycin, and lansoprazole plus amoxicillin, no adverse reactions peculiar to these drug combinations were observed. Adverse reactions that have occurred have been limited to those that had been previously reported with lansoprazole, amoxicillin, or clarithromycin.

Triple Therapy

Lansoprazole/Amoxicillin/Clarithromycin

The most frequently reported adverse reactions for patients who received triple therapy for 14 days were diarrhea (7%), headache (6%), and taste perversion (5%). There were no statistically significant differences in the frequency of reported adverse reactions between the 10 and 14 day triple therapy regimens. No treatment-emergent adverse reactions were observed at significantly higher rates with triple therapy than with any dual therapy regimen.

Dual Therapy

Lansoprazole/Amoxicillin

The most frequently reported adverse reactions for patients who received lansoprazole three times daily plus amoxicillin three times daily dual therapy were diarrhea (8%) and headache (7%). No treatment-emergent adverse reactions were observed at significantly higher rates with lansoprazole three times daily plus amoxicillin three times daily dual therapy than with lansoprazole alone.

For information about adverse reactions with antibacterial agents (amoxicillin and clarithromycin) indicated in combination with lansoprazole delayed-release orally disintegrating tablets, refer to the Adverse Reactions section of their prescribing information.

6.4 Laboratory Values

The following changes in laboratory parameters in patients who received lansoprazole were reported as adverse reactions:

Abnormal liver function tests, increased SGOT (AST), increased SGPT (ALT), increased creatinine, increased alkaline phosphatase, increased globulins, increased GGTP, increased/decreased/abnormal WBC, abnormal AG ratio, abnormal RBC, bilirubinemia, blood potassium increased, blood urea increased, crystal urine present, eosinophilia, hemoglobin decreased, hyperlipemia, increased/decreased electrolytes, increased/decreased cholesterol, increased glucocorticoids, increased LDH, increased/decreased/abnormal platelets, increased gastrin levels and positive fecal occult blood. Urine abnormalities such as albuminuria, glycosuria, and hematuria were also reported. Additional isolated laboratory abnormalities were reported.

In the placebo-controlled studies, when SGOT (AST) and SGPT (ALT) were evaluated, 0.4% (4/978) and 0.4% (11/2677) patients, who received placebo and lansoprazole, respectively, had enzyme elevations greater than three times the upper limit of normal range at the final treatment visit. None of these patients who received lansoprazole reported jaundice at any time during the study.

In clinical trials using combination therapy with lansoprazole plus amoxicillin and clarithromycin, and lansoprazole plus amoxicillin, no increased laboratory abnormalities particular to these drug combinations were observed.

For information about laboratory value changes with antibacterial agents (amoxicillin and clarithromycin) indicated in combination with lansoprazole delayed-release orally disintegrating tablets, refer to the Adverse Reactions section of their prescribing information.

SPL MEDGUIDE SECTION

Medication Guide

**A type of kidney problem (acute tubulointerstitial nephritis).** Some people who take proton pump inhibitor (PPI) medicines, including lansoprazole delayed-release orally disintegrating tablets, may develop a kidney problem called acute tubulointerstitial nephritis that can happen at any time during treatment with PPI medicines including lansoprazole delayed-release orally disintegrating tablets. Call your doctor right away if you have a decrease in the amount that you urinate or if you have blood in your urine. 

**Diarrhea caused by an infection (****Clostridium difficile****) in your intestines.** Call your doctor right away if you have watery stools or stomach pain that does not go away. You may or may not have a fever. 

**Bone fractures (hip, wrist, or spine).** Bone fractures in the hip, wrist, or spine may happen in people who take multiple daily doses of PPI medicines and for a long period of time (a year or longer). Tell your doctor if you have a bone fracture, especially in the hip, wrist, or spine.

**Certain types of lupus erythematosus.** Lupus erythematosus is an autoimmune disorder (the body’s immune cells attack other cells or organs in the body). Some people who take PPI medicines, including lansoprazole delayed-release orally disintegrating tablets, may develop certain types of lupus erythematosus or have worsening of the lupus they already have. Call your doctor right away if you have new or worsening joint pain or a rash on your cheeks or arms that gets worse in the sun. 

4 weeks for the healing and symptom relief of duodenal ulcers. 

10 to 14 days with certain antibiotics to treat an infection caused by bacteria called H. pylori.

maintaining healing of duodenal ulcers. Lansoprazole has not been studied beyond 12 months for this purpose.

up to 8 weeks for the healing and symptom relief of stomach ulcers.

up to 8 weeks for the healing of stomach ulcers in people taking pain medicines called nonsteroidal anti-inflammatory drugs (NSAIDs). Lansoprazole has not been studied beyond 8 weeks for this purpose.

reducing the risk of stomach ulcers in people who are at risk of developing stomach ulcers with NSAIDs. Lansoprazole has not been studied beyond 12 weeks for this purpose.

up to 8 weeks to treat heartburn and other symptoms that happen with gastroesophageal reflux disease (GERD).   

up to 8 weeks for the healing and symptom relief of acid-related damage to the lining of the esophagus (called erosive esophagitis or EE). Your doctor may prescribe another 8 to 16 weeks of lansoprazole delayed-release orally disintegrating tablets for patients whose EE does not improve or whose symptoms return.

maintaining healing of EE. Lansoprazole has not been studied beyond 12 months for this purpose.

the long-term treatment of conditions where your stomach makes too much acid. This includes a rare condition called Zollinger-Ellison syndrome.

up to 12 weeks to treat heartburn and other symptoms that can happen with GERD.

up to 12 weeks for the healing and symptom relief of EE.

up to 8 weeks to treat heartburn and other symptoms that can happen with GERD.

up to 8 weeks for the healing and symptom relief of EE. 

allergic to lansoprazole, any other PPI medicine, or any of the ingredients in lansoprazole delayed-release orally disintegrating tablets. See the end of this Medication Guide for a complete list of ingredients in lansoprazole delayed-release orally disintegrating tablets.

taking a medicine that contains rilpivirine (EDURANT®, COMPLERA®, ODEFSEY®, JULUCA®) used to treat HIV-1 (Human Immunodeficiency Virus).

have low magnesium, calcium, potassium or sodium levels in your blood or you are taking a diuretic.

have liver problems.

have phenylketonuria. Lansoprazole delayed-release orally disintegrating tablets contain aspartame.

are pregnant, think you may be pregnant or plan to become pregnant. Lansoprazole delayed-release orally disintegrating tablets may harm your unborn baby. Talk to your doctor about the possible risks to an unborn baby if lansoprazole delayed-release orally disintegrating tablets are taken during pregnancy.

are breastfeeding or plan to breastfeed. It is not known if lansoprazole passes into your breast milk. Talk to your doctor about the best way to feed your baby if you take lansoprazole delayed-release orally disintegrating tablets. 

Take lansoprazole delayed-release orally disintegrating tablets exactly as prescribed by your doctor.

Do not change your dose or stop taking lansoprazole delayed-release orally disintegrating tablets without talking to your doctor.

Take lansoprazole delayed-release orally disintegrating tablets before meals.

The lansoprazole delayed-release orally disintegrating tablet is a tablet that melts in your mouth with or without water.

**Do not break, cut, crush or chew the tablets.**

See the “Instructions for Use” at the end of this Medication Guide for instructions on how to mix and give lansoprazole delayed-release orally disintegrating tablets through a syringe and NG tube.

If you miss a dose of lansoprazole delayed-release orally disintegrating tablets, take it as soon as you remember. If it is almost time for your next dose, do not take the missed dose. Take your next dose at your regular time. Do not take 2 doses at the same time.

If you take too many lansoprazole delayed-release orally disintegrating tablets, call your doctor or your poison control center at 1-800-222-1222 right away or go to the nearest hospital emergency room.

**See “What is the most important information that I should know about lansoprazole delayed-release orally disintegrating tablets?”.**

**Low vitamin B12 levels** in the body can happen in people who have taken lansoprazole delayed-release orally disintegrating tablets for a long time (more than 3 years). Tell your doctor if you have symptoms of low vitamin B12 levels, including shortness of breath, lightheadedness, irregular heartbeat, muscle weakness, pale skin, feeling tired, mood changes, and tingling or numbness in the arms and legs.

**Stomach growths (fundic gland polyps).** People who take PPI medicines for a long time have an increased risk of developing a certain type of stomach growth called fundic gland polyps, especially after taking PPI medicines for more than 1 year.

**Low magnesium levels in the body**can happen in people who have taken lansoprazole for at least 3 months. Tell your doctor right away if you have symptoms of low magnesium levels, including seizures, dizziness, irregular heartbeat, jitteriness, muscle aches or weakness, and spasms of hands, feet or voice.

**Severe skin reactions.**Lansoprazole can cause rare but severe skin reactions that may affect any part of your body. These serious skin reactions may need to be treated in a hospital and may be life threatening: 

Skin rash which may have blistering, peeling or bleeding on any part of your skin (including your lips, eyes, mouth, nose, genitals, hands or feet).

You may also have fever, chills, body aches, shortness of breath, or enlarged lymph nodes. 
Stop taking lansoprazole delayed-release orally disintegrating tablets and call your doctor right away. These symptoms may be the first sign of a severe skin reaction.

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Instructions for Use
Lansoprazole Delayed-Release Orally Disintegrating Tablets
(lan soe′ pra zole)

Important:

•

Take lansoprazole delayed-release orally disintegrating tablets before meals.

•

**Do not** crush or chew lansoprazole delayed-release orally disintegrating tablets.

•

**Lansoprazole delayed-release orally disintegrating tablets should only be used with water as listed below.**

Lansoprazole Delayed-Release Orally Disintegrating Tablets:

**Do not** chew, crush, cut or break the tablets.

Put the tablet on the tongue and let it dissolve, with or without water. 

Swallow after the tablet dissolves.

The tablet usually dissolves in less than 1 minute.

For patients who have trouble swallowing tablets, lansoprazole delayed-release orally disintegrating tablets can be given as follows:

Giving lansoprazole delayed-release orally disintegrating tablets with water using an oral syringe:

Put a 15 mg tablet in an oral syringe and draw up 4 mL of water into the oral syringe, or put a 30 mg tablet in an oral syringe and draw up 10 mL of water into the oral syringe.

Gently shake the oral syringe to mix the tablet and the water.

After the tablet is mixed in the water, place the tip of the oral syringe in the mouth. Give the medicine within 15 minutes of mixing. Do not save the tablet and water mixture for later use.

Refill the oral syringe with about 2 mL of water for the 15 mg tablet or 5 mL of water for the 30 mg tablet, and shake gently. Place the tip of the oral syringe in the mouth and give the medicine that is left in the syringe.

Giving lansoprazole delayed-release orally disintegrating tablets with water through a nasogastric tube (NG tube) size 8 French or larger:

Put a 15 mg tablet in a catheter-tip syringe and draw up 4 mL of water, or put a 30 mg tablet in a catheter-tip syringe and draw up 10 mL of water.

Gently shake the catheter-tip syringe to mix the tablet and the water.

Connect the catheter-tip syringe to the NG tube.

Give the mixture right away through the NG tube that goes into the stomach. Give the medicine within 15 minutes of mixing. Do not save the pellets and water mixture for later use.

Refill the catheter-tip syringe with about 5 mL of water and shake gently. Flush the NG tube with the water.

How should I store lansoprazole delayed-release orally disintegrating tablets?

•

Store lansoprazole delayed-release orally disintegrating tablets at room temperature between 20° to 25°C (68° to 77°F). 

Keep lansoprazole delayed-release orally disintegrating tablets and all medicines out of the reach of children.

This Instructions for Use has been approved by the U.S. Food and Drug Administration.

The brand names listed are trademarks of their respective owners.

Manufactured for:
Mylan Pharmaceuticals Inc.
****Morgantown, WV 26505 U.S.A.

Manufactured by:
Mylan Laboratories Limited
****Hyderabad — 500 096, India

75102578

Revised: 3/2024
MX:LANSOD:R8Umh/MX:MG:LANSOD:R8mh

HOW SUPPLIED SECTION

16 HOW SUPPLIED/STORAGE AND HANDLING

Lansoprazole Delayed-Release Orally Disintegrating Tablets are available containing 15 mg or 30 mg of lansoprazole, USP.

The 15 mg tablets are pale yellow, round, flat-faced, speckled, unscored tablets debossed withM on one side of the tablet andLP1 on the other side. They are available as follows:

NDC 0378-6981-88
cartons of 100 unit-dose tablets (10 x 10)

The 30 mg tablets are pale yellow, round, flat-faced, speckled, unscored tablets debossed withM on one side of the tablet andLP2 on the other side. They are available as follows:

NDC 0378-6982-88
cartons of 100 unit-dose tablets (10 x 10)

Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]

Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.

PHARMACIST: Dispense a Medication Guide with each prescription.